The use of radiopharmaceuticals for diagnostic imaging has evolved significantly over the last decade. There has been a substantial research and development effort directed not only to identification and development of radiopharmaceutical agents themselves, but as well to the development of the electronics hardware used for detecting and displaying radiotracer images of targeted organs/tissue. While tissue imaging techniques have been developed utilizing a wide variety of radioactive elements, those that have received most attention are radiopharmaceuticals formed with gamma or positron emitting radionuclides. The use of positron emitting radiopharmaceuticals has been of particular research interest. Indeed, positron emission tomography ("PET") has been shown to be a most powerful medical imaging technique that can quantitatively map the spatial distribution of positron-emitting nuclides inside the living body. Currently, PET imaging studies of regional perfusion in the brain and heart have found applications both in biomedical research and in clinical practice. In studies of the heart with PET, assessment of myocardial perfusion and perfusion reserve after exercise or pharmacologic coronary vasodilation has been useful both diagnostically and for research evaluation of patients with coronary artery disease.
The clinical applications of PET and other radiotracer imaging techniques have been limited both by the availability of the required radionuclides and by the inherent biodistribution properties of radiopharmaceutical agents. Thus, for example, high definition imaging of heart tissue requires not only efficient myocardial uptake of the radiopharmaceutical agent but, as well, retention of the radioactivity in the targeted issue. The ideal radiopharmaceutical agent exhibits a biodistribution pattern which will provide higher concentrations of the radiopharmaceutical in the targeted tissue relative to the blood levels and relative to radiopharmaceutical concentration in adjacent non-targeted tissues. Thus, the significant properties of radiopharmaceuticals designed for imaging the heart are high myocardial tissue uptake, good heart/blood ratios, and prolonged retention of the radiopharmaceutical concentrations in the myocardial tissues relative to that in the blood and of other tissues/organs in the thoracic cavity.
It is one object of this invention to provide metal chelating ligand intermediates for the production of radiopharmaceuticals uniquely adapted for myocardial imaging.
It is another object of this invention to provide lipophilic, cationic, radioactive metal complexes for radiotracer imaging of the heart.
Still another, more specific embodiment of this invention is the preparation and use of positron emitting, lipophilic, cationic complexes for myocardial imaging.
Those and other embodiments of this invention are achieved by use of bis(salicylaldimine) type ligands derived from linear triamines or tetraamines. The novel ligands are used to prepare physiologically stable, lipophilic, cationic complexes with radioactive metal ions (M.sup.+i, i.gtoreq.3) which complexes exhibits biodistribution characteristics favorable for myocardial tissue imaging. The ligand complexing radioactive metal ions can be gamma emitters or more preferably, positron emitters, including most preferably gallium or indium positron-emitting radionuclides. The cationic complexes in accordance with this invention exhibit kinetic inertness toward exchange with the plasma protein transferrin and are stable in aqueous solutions at physcological pH.
Following intravenous injection the radioactive cationic complexes in accordance with this invention exhibit significant uptake into myocardial tissues. The rapid myocardial uptake is followed by prolonged mycocardial retention relative to blood and other proximal tissues, allowing delayed imaging as well as prolonged image acquisition. Preferred radiopharmaceuticals in accordance with this invention are positron emitting gallium-68 cationic complexes which, when used in conjunction with a .sup.68 Ge/.sup.68 Ga parent/daughter radionuclide generator system, will allow PET imaging studies of the heart, avoiding the expense associated with operation of an in-house cyclotron for radionuclide production.